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Preparation method of (-)-Cytoxazone and (+)-4-epi-Cytoxazone

A technology of inhibitors and cells, applied in the field of medicine, can solve problems such as poor stereoselectivity, harsh reaction conditions, and low total yield

Inactive Publication Date: 2021-11-12
SHENZHEN ELDERLY MEDICAL RES INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the synthesis route of Cytoxazone reported in the literature currently has problems such as expensive reagents, poor stereoselectivity, inconvenient experimental operation, harsh reaction conditions, and long route resulting in low overall yield, which is difficult to meet various research needs.

Method used

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  • Preparation method of (-)-Cytoxazone and (+)-4-epi-Cytoxazone
  • Preparation method of (-)-Cytoxazone and (+)-4-epi-Cytoxazone
  • Preparation method of (-)-Cytoxazone and (+)-4-epi-Cytoxazone

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Embodiment

[0090] The preparation method of (-)-Cytoxazone and (+)-4-epi-Cytoxazone of the present invention uses D-p-hydroxyphenylglycine as the starting material, and finally obtains the target product through four major steps. The reaction scheme is as follows:

[0091]

[0092] (1) Synthesis of compound 4

[0093] Dissolve compound 1 (D-p-hydroxyphenylglycine, 10g, 60mmol) in methanol (150mL), cool in an ice-water bath to 0°C, slowly add thionyl chloride (13mL, 180mmol) dropwise, and heat up to reflux after 30 minutes of dropping After reacting for 3h, it was concentrated under reduced pressure to obtain intermediate 2.

[0094]

[0095] Intermediate 2 was dissolved in tetrahydrofuran / water mixed solvent (1:1, 200mL), solid sodium bicarbonate (15.1g, 180mmol) and equivalent Boc anhydride (13.8mL, 60mmol) were added, reacted at room temperature for 10h, and Concentrate under reduced pressure, extract three times with ethyl acetate (200 mL), combine the organic phases, wash wit...

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Abstract

The invention discloses a preparation method of (-)-Cytoxazone and (+)-4-epi-Cytoxazone, which comprises the following steps: taking D-p-hydroxyphenylglycine as a raw material, carrying out methyl esterification reaction under the catalysis of thionyl chloride to obtain an intermediate 2, and then protecting amino with Boc anhydride to obtain an intermediate 3; taking potassium carbonate as alkali, and conducting reacting with methyl iodide under the reflux condition of acetonitrile to obtain a compound 4; reducing methyl ester by using a sodium borohydride / lithium chloride system to obtain a primary alcohol compound 5; and oxidizing primary alcohol by using IBX to obtain an intermediate 6, carrying out an SN2 reaction on the intermediate 6 and acetone cyanohydrin to obtain an intermediate 7, carrying out reflux by using a methanol solution of hydrogen chloride to obtain an intermediate 8, carrying out a reaction on the intermediate 8 and triphosgene to obtain two five-membered ring compounds 9 and 10, and carrying out reduction by using sodium borohydride to obtain (-)-Cytoxazone and an isomer (+)-4-epi-Cytoxazone. The synthetic route is convenient to operate.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a preparation method of (-)-Cytoxazone and its isomer (+)-4-epi-Cytoxazone, which are specific inhibitors of Th2 cell type II cytokines. Background technique [0002] Cytoxazone compounds have four isomers, among which (-)-Cytoxazone is a natural product. [0003] (-)-Cytoxazone is a microbial metabolite isolated from Streptomyces sp. in Hiroshima. Both it and the diastereoisomer (+)-4-epi-Cytoxazone can selectively inhibit the production of type II cytokines by Th2 cells (ineffective against Th1 cells), so they have good application prospects and can be used to treat a series of Diseases of cytokine imbalance, such as malignant lymphoma, rheumatic immune system diseases, etc. [0004] Compared with (-)-Cytoxazone, (+)-4-epi-Cytoxazone has stronger antibacterial activity against Gram-positive bacteria (Bacillus subtilis) and Gram-negative bacteria (Escherichia coli). [0005...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/24
CPCC07D263/24C07B2200/07
Inventor 吴正治龙伯华胡胜全汪梦霞李利民李子雯
Owner SHENZHEN ELDERLY MEDICAL RES INST
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